Acquired Immunodeficiency Syndrome (AIDS) is one of the most fatal disorders for which no completely successful chemotherapy has been developed so far. Human Immunodeficiency Virus (HIV), a retrovirus, is responsible for inducing AIDS. Protease enzyme encoded by HIV-1 is one of the major targets for the development of new chemotherapeutic agents. To expedite the search for a suitable more potent anti-HIV-1 inhibitor, we propose to conduct a detailed Quantitative Structure-Activity Relationship (QSAR) study of anti-HIV-1 protease inhibitors. We plan to develop QSAR models for HIV-1 protease inhibitors synthesized so far. Since the presence of a hydrophobic channel at the binding site of protease enzyme is well established, the in-depth study of the role of hydrophobicity of substituents of the ligands in the inhibition of the enzyme will be conducted. We will also carry out the lateral validation of our models using Comparative QSAR. This study will provide important lead(s) for the development of more potent anti-HIV-1 drugs with lesser side effects.